PROJECT SUMMARY Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer- related deaths in the United States. Mutations in components of the Wnt/?-catenin signaling pathway are found in 90% of spontaneously arising CRCs. These mutations lead to accumulation of the ?-catenin transcriptional co-activator in the nucleus and deregulated expression of Wnt/?-catenin target genes, including Axis inhibition two (AXIN2). The predominant role of AXIN2 has been described as a cytoplasmic protein that serves to mitigate Wnt signaling by targeting ?-catenin for proteasomal degradation. However, in CRCs, we find that AXIN2 localizes both to cytoplasmic and nuclear compartments. We have found that AXIN2 directly represses expression of the c-MYC proto-oncogene by forming a ternary complex with ?-catenin and T-cell factor (TCF) transcription factors at Wnt responsive DNA regulatory elements (WREs) in proximity to MYC. We therefore hypothesize that nuclear AXIN2 regulates Wnt/?-catenin target gene expression to promote tumorigenesis. In Aim 1, we will define the compendium of Wnt/?-catenin target genes regulated by nuclear AXIN2 and mechanistically assess how AXIN2 regulates their expression. In Aim 2, we will evaluate whether nuclear AXIN2 regulates the oncogenic potential of established human CRC cell lines. This work will further elucidate how oncogenic Wnt/?-catenin signaling controls gene expression and may lead to discovery of novel genes and pathways of potential therapeutic relevance.